We intend to define the genetic changes that are responsible for the pathogenesis of B-CLL and to correlate such changes to the clinical behavior of the leukemia and its response to treatment. The project has four specific aims that form the different genetic changes responsible for B-CLL initiation and progression. 1) We intend to define the role of CLL1, a novel putative tumor suppressor gene, in the pathogenesis of B-CLL and in the response to treatment. 2) We intend to determine the role of HMGI-G in the progression of B- CLL and whether self fusion of HMGI3 is involved in the development of CLL with trisomy of chromosome 12 or a normal karyotype. 3) We intend to determine whether the FHIT gene at 3p14.2 plays a role in the progression of B-CLL, and 4) We intend to determine whether the ATM and CLL1 genes play a role in the pathogenesis of familial CLL. The achievement of these goals will revolutionize our understanding of the mechanisms involved in the pathogenesis of B-CLL and will provide the basis for new approaches to the treatment of B-CLL.